A large number of antibiotics are employed therapeutically for treating infectious diseases caused by bacteria. However, the pathogens are becoming increasingly resistant to the drugs employed. Indeed, there is even the threat of serious danger arising due to what are termed multiresistant organisms, which have not merely become resistant to single antibiotic groups, such as β-lactam antibiotics, glycopeptides or macrolides, but in fact carry several resistances simultaneously. There even exist pathogens which have become resistant to all the antibiotics which are commercially available. It is no longer possible to treat infectious diseases which are caused by these organisms. For this reason, there is a great need for new compositions which can be used against resistant organisms While many thousands of antibiotics have been described in the literature, most of them are too toxic to be used as drugs.
The cell walls of Gram-positive and Gram-negative bacteria consist, for the most part, of peptidoglycan (murein), which, as what is termed the murein sacculus, encloses the cell completely and lends it mechanical stability as well as helping to determine its morphological form. Peptidoglycan is a macromolecule which is composed of an alternating sequence of the 1,4-β-glycosidically linked amino sugars, N-acetylglucosamine and N-acetylmuramic acid. Crosslinkings by way of short peptide bridges provide the sugar chains with a high degree of stability. The biosynthesis of peptidoglycan is catalyzed by a number of enzymes which are either dissolved in cytoplasm or else membrane-bound. Many of these enzymes are specific to bacteria, and represent ideal points of attack in the search for new antibiotics.
The bifunctional bacterial N-acetylglucosamine-1-phosphate uridyltransferase (GlmU) catalyzes the formation of UDP-N-acetylglucosamine from glucosamine-1-phosphate in a two-step reaction. UDP-N-acetylglucosamine is a fundamental building block in bacterial cell wall biosynthesis; accordingly, inhibiting its formation is therefore a promising route for finding novel antibacterial therapeutic agents (Sulzenbacher et al., J. Biol. Chem. 2001, 276 (15), 11844–11851).
There have already been reports of compounds from cultures of Aspergillus flavipes, such as flavipin (Raistrick et al., Biochem. J. 1956, 63, 395), which has been described as being an inhibitor of the respiratory chain, and the phytotoxin flavipucine (Findlay et al., J. C. S. Perkin I 1972, 2071) as well as the compound F-90558 (Kuraya et al., JP 20012862292 A2), which have been described as being antineoplastic agents. Pyrimidin-2-ylamine-substituted phenylbenzofurans are described, for example, in Burri et al., WO 02/10156.